Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA), glutamate and aspartate, at the N-methyl-D-aspartate (NMDA), the alfa-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, the quisqualate receptor and the kainate receptor. This excitotoxic action is responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or haemorrhagic stroke, cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma as well as lathyrism, Alzheimer's, and Huntington's diseases.
The compounds of the present invention may also be useful in the treatment of schizophrenia, Parkinsonism, epilepsy, anxiety, pain and drug addiction.
Most, if not all antagonists of the excitatory amino acids, including glutamate, as well as glutamate antagonists at the AMPA and/or kainate receptors have demonstrated limited, but still significant in vivo activity, for example as demonstrated by their ability to antagonize AMPA induced convulsions. Therefore there is a still unmet need for the identification of in vivo potent glutamate antagonists.